ABSTRACT A safe, effective vaccine remains the best hope for eradicating HIV-1, which now infects 37 million people worldwide and results in more than 1.2 million deaths and 1.8 million new infections each year. The only HIV-1 vaccine clinical trial to show vaccine efficacy was RV144, which achieved 31% protection from infection. Follow-on analyses identified immunological correlates of reduced risk of infection, finding that vaccine protection was not associated with neutralizing antibodies. Rather, protection was associated with non- neutralizing antibody activity, i.e., antibody effector function that is mediated through the constant Fc region. As such, there is intense interest in developing vaccines that can recapitulate and enhance the types of functional antibodies that were found in RV144. However, a gap exists in our knowledge of how such responses can best be elicited by vaccination, and how Fc-mediated activity is induced, evolves and endures. It is not clear what effect vaccine modalities have on this process, nor how it can be optimized. In this proposal, we aim to discover the most optimal methods by which Fc-mediated activity can be elicited by vaccines. We will assess several vaccine parameters, including antigen, adjuvant, route of inoculation, and prime/boost strategies. Importantly, we will use novel cutting edge, high throughput technologies to define the ontogeny, kinetics, evolution and duration of Fc antibody responses in unprecedented detail and breadth. Further, we will define the relationship between vaccine-elicited Fc-mediated function and the antigenic landscape of Env. Our goal is to gain fundamental immunological insights into how vaccines drive Fc-related antibody responses, and how vaccination modalities can be optimized to elicit highly functional, durable antibody responses against HIV-1. If successful, these findings would guide the development of the next generation of vaccines moving into the clinic, and would represent a significant step forward for HIV-1 vaccine development, and.